Parkinson's disease (PD) affects nearly 3% of individuals over the age of 65 and is the second most common neurodegenerative disease in the United States. Recently, there is an increasing appreciation for the role of inflammation and microglia in the progression of PD. 1-Synuclein is a widely distributed 140 amino acid protein in brain associated with PD and other neurodegenerative disorders, but its role in brain physiology is poorly understood. There is ample evidence, by us and others, which demonstrates that 1-synuclein has a profound impact on lipid-mediated signal transduction and on brain lipid metabolism. Lipid-mediated signaling is a critical component of the regulatory pathway for microglial activation; however, the role of 1-synuclein in modulating microglia activation state via the regulation of lipid-mediated signal transduction is poorly defined. This is important because we have recently discovered a novel link between 1-synuclein and microglial activation state. We will use two complimentary approaches in this proposal to address the role of 1-synuclein in neuroinflammatory response via its regulation of these lipid-mediated signaling pathways by using cultured microglia to determine mechanisms underlying this aberrant phenotype and extending these observations to the intact mouse subjected to neuroinflammatory insult. Understanding how 1-synuclein and its mutant forms affects microglial activation will offer insight into the pathophysiology of the inflammatory response in PD. We will address our Central Hypothesis that 1-synuclein expression modulates microglia activation by regulating multiple lipid-mediated signaling pathways by completion of the following specific aims: Specific Aim 1: Determine the extent that wt and A53T 1-synuclein expression modulates lipid mediated microglial activation Specific Aim 2: Resolve the extent to which wt and A53T 1-synuclein expression impacts lipid mediated signaling and microglial activation in vivo The proposed work is innovative because it examines a novel function of 1-synuclein and its mutant form (A53T) in regulating microglial activation through its ability to modulate cellular lipid metabolism. It is our expectation that these results will identify a key role for 1-synuclein in facilitating prostaglandin formation, PLD "and PLA2 activity, thereby regulating downstream lipid metabolism and microglial activation, both in cultured cells and in vivo. These results will be significant because they will demonstrate a pivotal role for 1-synuclein "in regulating microglial activation and thus brain inflammatory response. This will provide the fundamental foundation required to address the role that 1-synuclein and its mutant forms have in brain inflammatory "response, extending our understanding of how 1-synuclein modulates cellular lipid metabolism, thereby impacting neurodegenerative disease pathophysiology. PUBLIC HEALTH RELEVANCE The relevance of our proposed work is that it examines a novel function of 1-synuclein in regulating brain neuroinflammatory response through its ability to modulate lipid-mediated microglial activation pathways. This is important because of: 1). the poorly defined function of 1-synuclein in the brain; 2). the association of 1- synuclein with a large number of neurodegenerative diseases; and 3). the known association of inflammatory response in these neurodegenerative diseases. Results from this project will be significant because they will demonstrate a pivotal role for 1-synuclein in regulating brain neuroinflammatory response, extending our understanding of how 1-synuclein modulates cellular lipid metabolism, thereby increasing our understanding of how 1-synuclein impacts neurodegenerative disease pathophysiology. [unreadable] [unreadable] [unreadable]